Modern treatments with highly active antiretroviral therapy (HAART) regimens result in HIV suppression and immune recovery, however the prevalence of HIV-Associated Neurocognitive Disorders (HAND) and neurodegeneration has remained the same or increased. During the previous period of funding we showed that abnormal activation of cyclin dependent kinase-5 (CDK5) plays a key role in HIV. We also demonstrated that abnormal activation of CDK5 promotes neurodegeneration via accumulation of TAU and collapsin response mediator protein-2 (CRMP2), a novel target in HAND. Remarkably, knockdown of CDK5 reduced the deficits in a gp120 tg model. For the renewal the main objectives will be; a) to better understand the cellular mechanisms through which HIV proteins promote nucleo-cytoplasmic translocation and pathological activation of CDK5 leading to TAU/CRMP2 mediated neurotoxicity, and b) to determine if TAU reduction or CDK5 inhibition with a new class of CDK5 inhibitors that penetrate the BBB is neuroprotective in preclinical models of HIV neurotoxicity. Our central hypothesis is that HIV proteins such as trans-activator of transcription (Tat) and gp120 modulate cell cycle regulators and interfere with the subcellular localization of CDK5. CDK5 nucleo-cytoplasmic translocation could promote the neurotoxic phosphorylation of CDK5 substrates such as TAU and CRMP2. Therefore strategies to modulate CDK5 or reduce TAU might represent novel therapeutic interventions for HAND. For this purpose we propose the following Aims: Aim 1: To elucidate the role of CDK5 translocation and TAU/CRMP2 phosphorylation in the cellular mechanisms of HIV neurotoxicity. Aim 2: To determine whether TAU reduction in vivo ameliorates the neurodegenerative and behavioral deficits in tg rodent models of HIV neurotoxicity. Aim 3: To evaluate the neuroprotective effects of novel and more specific CDK5 inhibitor which reduce TAU/CRMP2 phosphorylation in tg models of HIV neurotoxicity. This new direction represents a natural extension from the previous period of funding and provides a new avenue that might lead to the development of a novel class of HIV neuroprotective drugs.